This application entitled "Genes and Phenotype (GAP): A national resource for genotype-phenotype studies of immunologic and inflammatory pathways". The applicants and their collaborating investigators have developed a unique population resource of 4,500 normal subjects who can be characterized genetically and are willing to be repeatedly studied for immunologically related phenotypes. We propose to make this population resource, the GAP cohort, available to the scientific community on a national basis. In specific aim 1, we will formalize and expand an existing infrastructure for consenting, re-contacting and studying this population. The entire cohort will be characterized for approximately 12,000 SNPs of potential immunological interest. This will permit functional studies of genotype-phenotype correlations in an efficient manner. We will establish "working groups" of scientists with interests in particular aspects of immunobiology to guide the efficient utilization of the resource. In specific aim 2, we will utilize the GAP cohort to carry out detailed studies of genetic variations that impact B cell biology. We will specifically address a "two hit" hypothesis for autoimmune susceptibility at the B cell level. We propose that genetic polymorphisms in intracellular signaling molecules such as Blk, Csk, and PTPN22 influence early B cell development towards increased autoreactivity through lack of negative selection (the "first hit"). We also propose to investigate the role of FcR and CD22 pathways in the predisposition to B cell hyper-reactivity in later stages of B cell development (the "second hit"). These B cell studies will illustrate the utility of the GAP cohort for understanding the complex multifactorial pathways involved in human autoimmune diseases. .